Introduction: Optimal vital signs monitoring of patients with severe sepsis in resource-limited settings may improve outcomes. The objective of this study was to determine the frequency of vital signs monitoring of patients with severe sepsis and its association with mortality in a regional referral hospital in Uganda. Methods: We reviewed medical records of patients admitted to Mbarara Regional Referral Hospital in Southwestern Uganda with severe sepsis defined by the presence of infection plus ≥2 of the systemic inflammatory response syndrome criteria, and ≥1 organ dysfunction (altered mental state, hypotension, jaundice, or thrombocytopenia). We recorded frequency of vital signs monitoring in addition to socio-demographic, clinical, and outcome data. We analyzed the data using logistic regression. Results: We identified 202 patients with severe sepsis. The median age was 35 years (IQR, 25–47) and 98 (48%) were female. HIV infection and anemia was present in 115 (57%) and 83 (41%) patients respectively. There were 67 (33%) in-hospital deaths. The median monitoring frequency per day was 1.1 (IQR 0.9–1.5) for blood pressure, 1.0 (IQR, 0.8–1.3) for temperature and pulse, and 0.5 (IQR, 0.3–1.0) for respiratory rate. The frequency of vital signs monitoring decreased during the course of hospitalization. Patients who died had a higher frequency of vital signs monitoring (p<0.05). The admission respiratory rate was associated with both frequency of monitoring (coefficient of linear regression 0.6, 95% CI 0.5–0.8, p<0.001) and mortality (AOR 2.5, 95% CI 1.3–5.3, p = 0.01). Other predictors of mortality included severity of illness, HIV infection, and anemia (p<0.05). Conclusions: More research is needed to determine the optimal frequency of vital signs monitoring for severely septic patients in resource-limited settings such as Uganda.